We previously found an association between overexpression of NF-kB related genes, altered expression of TGFb receptor (TBR) subunits and downstream targets in head and neck squamous cell carcinoma (HNSCC). During the prior year we reported that TGFbeta receptor I/ phosphastase tensin (Tgfbr1/Pten) are frequently decreased in HNSCC, and conditional double knockout mice for these genes develop HNSCC that exhibit increased PI3K-Akt pathway and NF-kappaB/REL activation (Bian, Oncogene, 2012). We report the potential of PI3K-mTOR inhibitor for prevention of tumor development in these Tgfbr1/Pten dko mice and therapy of human xenograft bearing mice (Herzog, Bian et al., Clin Cancer Res, 2013). We found that PI3K-mTOR antagonist inhibited downstream progrowth signaling, reactivated tumor suppressor TP53, and sensitized tumors to cytotoxic chemotherapy and radiation. As co-recipients of an NIH Director's Bench to Bedside Award in collaboration with NIDCR investigators, we are conductinga pilot clinical study of neoadjuvant mTOR inhibitor rapamycin in patients with advanced HNSCC (NIH protocol 10-D-180). 10 subjects have been accrued to date. Heat Shock Protein 90 inhibitors target many oncoproteins in the signal network we have shown is co-activated in HNSCC. In collaborative studies, we recently reported that HSP90 inhibitors target overexpressed Epidermal growth factor receptor, downstream signaling, and strongly inhibit human HNSCC xenografts (Ahsan et al., Neoplasia, 2012). We report that HSP90 inhibitor SNX5422/2112 in phase I studies at NIH broadly inhibited oncogenic signal and transcription factors and reactivates wild type p53 in human HNSCC lines and tumor xenograft models (Friedman et al., Translational Oncol, 2013). Inflammation and inflammatory signaling is implicated in promoting cancer development, including human head and neck squamous cell carcinomas (HNSCC). We recently demonstrated that NF-kB transcription factor c-REL interacts with TP53 family members DeltaNp63 and TAp73 to reciprocally activate inflammatory and cancer related genes, while repressing growth arrest and proapoptotic genes in HNSCC (Lu, Cancer res, 2011; Yang, Cancer Res, 2011). Together, these findings suggest signal regulation coordinating NF-kB, p63 and p73 interactions and function may be important in pathogenesis and as targets for prevention and therapy. Candidate kinases regulating NF-kB and TAp73 in SCC cancer stem cells has been identified as potential targets for therapy.